Gastrointestinal and cardiovascular health are intimately linked, yet the mechanism by which diet-derived lipid metabolites and the gut microbial flora impact efferent sympathetic nerve activity is largely unknown. Work from our laboratory and others? provides increasing evidence that the enteric nervous system directly influences the sympathetic control of systemic blood pressure. The viscerosensory-sympathetic network is a functional neural circuit connecting afferent sensory fibers of the gut and efferent vasoconstrictor neurons at the level of the spinal cord. While this neural circuitry likely influences systemic blood pressure in able-bodied individuals, its role in the development of severe hypertensive crises in patients living with spinal cord injury (SCI) is irrefutable. Autonomic dysreflexia (AD) is often a clinical emergency in SCI individuals and is characterized by paroxysmal hypertension in response to otherwise innocuous visceral stimuli (e.g. fecal impaction). Despite its obvious significance, mechanisms involved in the regulation of viscerosensory-sympathetic reflexes (VSSRs) are poorly understood. Our preliminary studies indicate that C-fiber sensory neurons expressing transient receptor potential cation channel V1 (TRPV1) are involved in the afferent limb of the viscerosensory-sympathetic circuitry. Our proposal seeks to (Aim 1) provide a mechanistic understanding of the role of diet-derived lipid mediators in exaggerating the AD phenotype, (Aim 2) interrogate novel therapeutic strategies for attenuating sympathetic hyperreflexia following SCI, and (Aim 3) define the role of SCI-associated gut dysbiosis in contributing to the production of pathogenic diet-derived lipid mediators. Our central hypotheses identify new pathogenic factors (dietary fatty-acid content and SCI-associated dysbiosis) and a biochemical mechanism (diet-derived TRPV1 lipid ligands) that may be independent targets for therapeutic intervention. Uniquely, our rationally designed therapeutic strategies target the major underlying cause of AD (i.e. visceral C-fiber hypersensitivity) rather than the symptomatic outcome (i.e. acute hypertensive crisis) and thus constitute a major paradigm shift.